Data are emerging to support the idea that factors and processes characteristic of angiogenesis are found in the Alzheimer disease (AD) brain. We have shown that in AD microvessels express or release many inflammatory, proangiogenic proteins. Despite increases in proangiogenic factors in the AD brain, evidence for increased vascularity is lacking. In our model we hypothesize that the angiogenic process does not progress to new vessel growth because an imbalance of pro- and anti-angiogenic factors results in aborted angiogenic signaling. In this project we test the hypothesis that AD microvessels express an anqiogenic phenotype and that this abnormal activation of brain endothelial cells is important for the development of AD pathology. Aim 1: To test the hypothesis that in AD brain microvessels become activated but fail to complete angiogenesis because an imbalance of pro- and anti-angiogenic factors results in aborted angiogenic signaling. Brain microvessels are isolated from AD patients, age-matched non-demented controls, and patients with inflammatory and non-inflammatory CMS disease. Isolated vessels are compared for expression of pro- and anti-angiogenic factors including thrombin, VEGF, endothelin-1 TGF-/0, nitric oxide, thrombospondin, and amyloid beta (A[unreadable]). The activities of signaling kinases phosphatidylinositol-3 kinase (PI3K)/Akt, p38 kinase, extracellular signal-regulated kinase (ERK), and c-Jun NH2-terminal kinase (JNK) are measured. Immunohistochemistry of brain sections is used to assess the spatial correlation of pro- and anti-angiogenic proteins with A/? deposition and AD pathology. Aim 2: To test the hypothesis that acquisition of the angiogenic phenotype contributes to the pathogenesis of AD pathology and cognitive impairment in animal models of AD. To determine the temporal association between acquisition of the angiogenic phenotype and the onset of disease, markers of angiogenesis are measured in isolated brain microvessels obtained from AD transgenic mice before the onset of cognitive changes and AD pathology and at several ages during disease progression. A causal link between the angiogenic phenotype and disease progression is evaluated using antiangiogenic drugs. Administration of these drugs to animals prior to the onset of behavioral changes and AD pathology will determine whether inhibiting the angiogenic phenotype affects the course of disease. Taken together, data from Aim 1 showing the clinical relevance of angiogenic changes in AD and results from Aim 2 demonstrating a causal link between the angiogenic phenotype and disease progression would argue strongly for a new therapeutic approach in AD. These results could be very exciting because the angiogenic brain endothelial cell is a novel, unexplored therapeutic target, and several antiangiogenic drugs are currently in use in Phase III clinical trials. Thus, clinical studies with angiogenesis inhibitors could be rapidly designed and implemented in AD patients.